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PubMed1987

Clinical trials of the Haemophilus influenzae type b capsular polysaccharide-diphtheria toxoid conjugate vaccine.

To date in the United States over 3000 subjects under 2 years of age have received 1 or more doses of PRP-D vaccine. Thus far there have been no statistically significant differences between the rate of local or systemic reactions among recipients of this vaccine and that among those who received the PRP or placebo control vaccines. The vaccine is well-tolerated and is not associated with clinically significant adverse reactions. The PRP-D vaccine has been shown to be a T cell-dependent immunogen, inducing sequential increases in antibody level with repeated immunization and producing a high proportion of IgG relative to IgM. A recall response, or immunologic memory effect, has been demonstrated in children 1 year after receiving PRP-D. PRP-D is consistently immunogenic in all age groups. In adults this vaccine induces a geometric mean antibody response greater than 200 micrograms/ml. In infants 7 to 24 months of age levels greater than 1 microgram/ml have been achieved in over 90% of the subjects with 1 or 2 doses of PRP-D, whereas 90% or more of infants under 7 months of age achieve levels of 0.15 microgram/ml or greater.

Adult↗

PubMed1997

Safety and immunogenicity of tetravalent pneumococcal vaccines containing 6B, 14, 19F and 23F polysaccharides conjugated to either tetanus toxoid or diphtheria toxoid in young infants and their boosterability by native polysaccharide antigens.

BACKGROUND: New vaccines against pneumococcal infections in infancy are needed. We assessed in young infants the safety and immunogenicity of two tetravalent vaccines containing pneumococcal 6B, 14, 19F and 23F polysaccharides conjugated to either tetanus toxoid (Pnc-T) or diphtheria toxoid (Pnc-D). METHODS: Pnc-T or Pnc-D containing 3 microg of polysaccharide of each of the four pneumococcal polysaccharides or placebo were given intramuscularly in a double blinded fashion (25 infants per group) at 2, 4 and 6 months of age. At 12 months of age all 75 children were boosted with a 23-valent nonconjugate polysaccharide pneumococcal vaccine. Serum type-specific anticapsular antibody concentrations were measured at 2, 4, 6, 7, 12 and 13 months of age. Adverse events occurring within 72 h after each injection were recorded. RESULTS: Both Pnc-T and Pnc-D were well-tolerated. Pnc-T and Pnc-D had higher antibody concentrations compared with placebo after primary immunity (type 6B, 1.66, 1.40 and 0.60 microg/ml, respectively; type 14, 4.81, 2.65 and 2.22 microg/ml, respectively; type 19F, 2.40, 3.48 and 0.83 microg/ml, respectively; type 23F, 0.96, 0.44 and 0.35 microg/ml, respectively). Proportions of infants with concentrations above 1.0 microg/ml were also higher in the vaccine recipients than in those given placebo. After booster with the nonconjugate polysaccharide vaccine, both geometric antibody concentration and proportion with concentrations > or =1.0 microg/ml were significantly higher among either Pnc-T or Pnc-D recipients than among placebo recipients. CONCLUSIONS: Both Pnc-T and Pnc-D were well-tolerated, induced serotype-specific anticapsular antibodies and induced immunologic memory.

Antibodies, Bacterial↗

PubMed1997

A glycoprotein pneumococcal conjugate vaccine primes for antibody responses to a pneumococcal polysaccharide vaccine in Gambian children.

BACKGROUND: Streptococcus pneumoniae is a major cause of acute respiratory infections and acute bacterial meningitis in children. Pneumococcal polysaccharide vaccines are poorly immunogenic in this highly vulnerable group, but protein polysaccharide conjugate vaccines are likely to be more effective. OBJECTIVES: To determine whether immunization of infants with a pneumococcal conjugate vaccine induces immunologic memory. METHODS: Eighty-four Gambian children, who had been vaccinated previously with two or three doses of a pentavalent pneumococcal conjugate vaccine (CRM197) or with a Haemophilus influenzae type b (Hib) conjugate vaccine were immunized when approximately 2 years old with a 23-valent pneumococcal polysaccharide vaccine, and a blood sample was obtained 10 days later. Pneumococcal antibody titers in prevaccination and postvaccination sera were measured by enzyme-linked immunosorbent assay and by an opsonophagocytic assay. RESULTS: On revaccination with a pneumococcal polysaccharide vaccine, children who had previously received pneumococcal conjugate vaccine had higher antibody concentrations to each of the five polysaccharide components of the conjugate vaccine than did control children. For type 6B polysaccharide, which is poorly immunogenic in young children, postvaccination antibody concentrations were 0.37, 27.6 and 50.9 microg/ml in children who had received no previous pneumococcal immunization or two or three doses of conjugate vaccine, respectively. Type 14 antibodies produced after revaccination were of high avidity and had opsonic activity. CONCLUSION: Vaccination of young infants with two or three doses of a pneumococcal conjugate vaccine primes the immune system to respond strongly and rapidly on subsequent exposure to pneumococcal polysaccharide.

Antibodies, Bacterial↗

PubMed1998

Haemophilus influenzae type b conjugate vaccines: a review of efficacy data.

BACKGROUND: The development of a vaccine against Haemophilus influenzae type b (Hib) was stimulated by its recognition as a major pathogen of early childhood. The first vaccine to be developed was composed of the capsular polysaccharide of the organism, polyribosylribitol phosphate (PRP), and although effective in older children, it failed to protect those <2 years of age, the group with the highest burden of disease. The conjugation of PRP to protein led to a group of vaccines with enhanced immunogenicity and the ability to induce immunologic memory and thus the potential to protect in infancy. OBJECTIVES: To review the trials of Hib conjugate vaccines in which protective efficacy in infants has been assessed and the experience in countries in which Hib conjugate vaccines have been introduced into the routine infant immunization schedule. DISCUSSION: Each of the Hib conjugate vaccines [PRP-diphtheria toxoid conjugate (PRP-D), PRP conjugated to outer membrane protein of Neisseria meningitidis group B (PRP-OMP), PRP oligosaccharides conjugated to mutant diphtheria toxin CRM197, (HbOC) and PRP conjugated to tetanus toxoid (PRP-T)] has been subjected to prospective clinical trials and all have demonstrated high protective efficacy with one exception: that of the least immunogenic vaccine, PRP-D, when used in a Native American population with a high level of natural disease. The trials have used different populations and different schedules, which limits conclusions about relative efficacies. However, it seems likely that all the vaccines are capable of high efficacy in populations with low levels and late age of Hib disease. Three vaccines (PRP-D, PRP-OMP, PRP-T) have been tested in populations with high rates of disease and only PRP-D has been found lacking. As predicted by immunogenicity data, PRP-OMP affords efficacy after one dose, and PRP-T is efficacious with an accelerated schedule. Of more practical significance the effectiveness of these vaccines when introduced into populations has been uniformly impressive. CONCLUSIONS: Particularly where vaccine coverage is high, it is now likely that Hib disease can be eliminated using Hib conjugate vaccines in infancy.

Bacterial Outer Membrane Proteins↗

PubMed2001

Serum and salivary anti-capsular antibodies in infants and children immunized with the heptavalent pneumococcal conjugate vaccine.

AIM: To study the ability of seven-valent experimental pneumococcal polysaccharide CRM197 protein conjugate vaccine (PncCRM) to induce antibodies in serum and saliva of infants. METHODS: Sixty Finnish infants received Pnc-CRM vaccine at 2, 4 and 6 months of age and were boosted with PncCRM (n = 30) or pneumococcal polysaccharide (PncPS) (n = 29) vaccine at the age of 15 months. Serum IgG antibody concentrations to vaccine serotypes 4, 6B, 9V, 14, 18C, 19F and 23F were measured by enzyme immunoassay at 2, 4, 6, 7, 15, 16 and 24 months of age. Salivary IgA, IgG and secretory Ig antibody titers at 7 and 16 months of ages were analyzed by enzyme immunoassay against the same serotypes, except 23F. RESULTS: PncCRM induced systemic immune responses and immunologic memory. At 7 months of age 69 to 100% of children, depending on the serotype, had serum IgG antibody concentrations exceeding the value of 1.0 microg/ml. At 15 months the titers were still higher than before the vaccinations. Booster doses of either PncPS or PncCRM induced an increase in antibody concentrations. The titers were still elevated at 24 months of age. Salivary IgA and IgG antibodies were found rarely at 7 months of age, but in up to 80% of samples taken at 16 months of age, depending on the serotype and nature of the booster vaccine. Salivary IgG correlated with IgG in serum, supporting the theory that salivary IgG is derived from serum. Salivary IgA and secretory Ig correlated positively, which indicates that IgA was locally produced. CONCLUSIONS: PncCRM induces both systemic and mucosal immune responses in infants.

Antibodies, Bacterial↗

PubMed2002

Haemophilus influenzae type b conjugate vaccine diluted tenfold in diphtheria-tetanus-whole cell pertussis vaccine: a randomized trial.

BACKGROUND: Despite their proven efficacy Haemophilus influenzae type b (Hib) conjugate vaccines are not given to most children in the developing world in the face of an estimated global Hib disease burden of nearly 2 million cases per annum. A major barrier to the introduction of the vaccine would be overcome by diluting the vaccine 10-fold in diphtheria-tetanus-whole cell pertussis (DTP). We report a randomized trial comparing the use of Hib conjugate vaccine diluted in a multidose vial of DTP with that of the full Hib dose. METHODS: We randomized 168 infants to receive either the full dose Hib polysaccharide-tetanus toxoid conjugate (PRP-T) vaccine or a 1/10 dilution prepared by reconstituting the full dose in a 10-dose DTP vial. Infants were vaccinated at 6, 10 and 14 weeks of age and received a full dose as a test of immunologic memory at 9 months of age. Sera were collected at each visit and at 1 week after the booster dose. Serum anti-capsular PRP antibody concentrations were measured by enzyme-linked immunosorbent assay. RESULTS: After the primary vaccination series, 95% of infants in the full dose arm and 94% of infants in the 1/10 dose arm achieved anti-PRP IgG antibody concentrations of > or = 1.0 microg/ml. Infants receiving the diluted vaccine had significantly higher titers of anti-PRP antibody in response to the booster dose (151.36 microg/ml vs. 68.55 microg/ml, P = 0.009). CONCLUSIONS: The 1/10 dose of PRP-T was as immunogenic and safe as the full dose. The technique of diluting a single dose of PRP-T in a 10-dose DTP vial could potentially allow the widespread introduction of Hib vaccine in resource-poor countries currently unable to afford full dose Hib conjugate vaccine.

Antibodies, Viral↗

PubMed2002

Mucosal immune responses to meningococcal conjugate polysaccharide vaccines in infants.

BACKGROUND: Serogroup C meningococcal conjugate polysaccharide vaccines have been reported to induce significant serum IgG antibodies and immunologic memory in infants. Because meningococcus is a mucosal pathogen colonizing the nasopharynx, local mucosal immune responses may play an important role in host defense against infection and carriage. We have investigated the mucosal IgA and IgG antibody responses to two meningococcal C conjugate vaccines in the saliva of healthy infants. METHODS: Specific salivary IgA and IgG antibodies to two meningococcal C polysaccharide conjugate vaccines (Menjugate from Chiron Corp., n = 46; and Meningitec from Wyeth Lederle, n = 54) were investigated by immunoassay in infants after parenteral vaccinations at the ages of 2, 3 and 4 months. Unstimulated saliva samples were collected immediately before the first immunization and 1 month after the third immunizations. Forty healthy infants receiving the same routine vaccines but no meningococcal C vaccine were recruited as controls. RESULTS: There were significant increases in meningococcal C polysaccharide-specific IgG antibody concentrations postvaccination compared with prevaccination concentrations in both vaccinated groups (both P < 0.001), but no change in the control group. There were no significant increases in specific IgA postvaccination geometric mean concentrations in either the vaccine or the control groups. The number of IgA positives postvaccination increased slightly in the Wyeth vaccine group vs. controls (P < 0.05). CONCLUSIONS: Significant salivary IgG antibodies to meningococcal C polysaccharide were observed after parenteral immunization with two meningococcal C conjugate vaccines, whereas there was no significant increase in specific IgA antibody levels for these two vaccines.

Antibodies, Bacterial↗

PubMed1990

Assessment of the lymphocyte response to silicone.

The biocompatibility of silicone is once again the focus of increased interest. Long considered inert, silicone has now been reported to be responsible for macrophage inhibition in rats and to possibly cause adjuvant disease in humans, and the related compound silica has elicited an antibody response in mice. The present study evaluates lymphocytic response to silicone as expressed by the demonstration of immunologic memory, or changes in specific lymphocyte subpopulations. Thirty-six female Lewis rats (250 gm body weight) were used as test animals. Group 1 (n = 12) was injected subcutaneously with 2.5 ml Freund's Complete Adjuvant (FCA) alone. Group 2 (n = 12) was injected with 2.5 ml FCA sonicated with silicone gel. Group 3 (n = 6) was injected with 2.5 ml FCA, and at 4 weeks, gel-filled silicone implants were placed subcutaneously. Group 4 (n = 6) was injected with 2.5 ml FCA sonicated with silicone gel, and gel-filled silicone implants were placed at 4 weeks. An additional group of six rats (group 5) served as control for the experimental animals, and a group of four rats (group 6) served as naive control. Groups 1 and 2 were sacrificed at 4 weeks, and splenic lymphocytes were obtained for lymphocyte transformation assays performed against silicone. Assays also were run with the addition of the known mitogens Con A, PHA, LPS, and pokeweed. Cytofluorographic analysis of pan-T, T-helper, T-suppressor, and B-cell populations was performed. Groups 3, 4, 5, and 6 were harvested at 8 months, and splenic lymphocytes were subjected to lymphocyte transformation assay.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2000

The relevance of donor T cell-directed immunoglobulin G in historic sera in the age of flow cytometry.

BACKGROUND: Renal transplant recipients with a positive historic cross-match due to donor T cell-directed IgG antibodies are considered to have decreased graft survival, even if their current serum is negative prior to transplantation. With the use of flow cytometric cross-match for testing current sera, false-negative results could be eliminated and the outcome of transplantation in this group of patients could be improved, assuming that immunological memory is effectively controlled with immunosuppression. METHODS: We reviewed our records to identify those patients who underwent cadaveric renal transplant, with a historic IgG positive cytotoxic T cell cross-match and a current negative flow cytometric T cell cross-match. RESULTS: Eighteen patients underwent cadaveric renal transplant in the face of a historic IgG positive T cell cross-match and a current negative flow cytometric T cell cross-match. In 14 patients treated with cyclosporine-based immunosuppression the 1-, 2-, and 3-year cumulative graft survival rates were 57, 50, and 43%, respectively. Ten of the 14 patients (71%) ultimately lost their grafts. CONCLUSIONS: Even with negative flow cytometric cross-match in current serum, a positive historic conventional cross-match suggests a high risk of graft failure.

Adolescent↗

PubMed2001

Role of reentry of in vivo alloMHC peptide-activated T cells into the adult thymus in acquired systemic tolerance.

BACKGROUND: T cell recognition of alloMHC peptide presented by self dendritic cells via the indirect pathway of allorecognition in the thymus induces T cell tolerance. Most recently we have shown that the i.v. administration of immunodominant Wistar Furth MHC class I (RT1.Au) peptide 5- (P5) pulsed myeloid or lymphoid dendritic cells induces operational tolerance to a fully MHC-mismatched cardiac allograft. This finding led us to hypothesize that circulation of peripheral P5-activated T cells to the thymus plays an important role in the induction of acquired tolerance. METHODS: We used the adoptive transfer of 111Indium-oxine- (111In-oxine) labeled P5-pulsed syngeneic dendritic cells and in vivo P5-activated syngeneic T cells to study the role of their circulation to the thymus in the induction of transplantation tolerance. RESULTS: Intravenously administered 111In-oxine-labeled naïve DC actively migrated to and localized in the liver and spleen but did not enter the lymph nodes, bone marrow, and thymus. In vitro peptide-pulsed dendritic cells had a similar pattern of tissue localization except for a modest number of myeloid but not lymphoid DC entering the thymus. The demonstration that adoptive transfer of in vivo peptide-primed T cells induces permanent graft survival in antilymphocyte serum transiently immunosuppressed syngeneic secondary hosts led us to examine the traffic of in vivo activated T cells. Whereas naïve syngeneic T cells preferentially homed to the peripheral lymphoid organs, they did not reenter the thymus. In contrast, in vivo peptide-activated peripheral T cells migrated to and accumulated in the thymus, thus confirming that reentry of T cells to the thymus is restricted to in vivo activated T cells. Although antilymphocyte serum immunosuppression significantly reduced circulation of primed T cells to the thymus, it did not completely abolish it, as seen with gamma-irradiated primed T cells. CONCLUSION: These findings provide the first formal evidence directly linking reentry of in vivo alloMHC peptide-activated T cells to the thymus with the induction and possibly maintenance of acquired antigen-specific tolerance. Our results suggest that the thymus is open to a two-way traffic with the periphery and may function as a repository of immunological memory.

Adoptive Transfer↗

PubMed1993

Haemophilus influenzae type b polysaccharide-protein conjugate vaccines in children.

Prevention of invasive infections caused by Haemophilus influenzae type b (Hib) bacteria has become possible with new vaccines. Covalent coupling to a protein carrier increases the immunogenicity of Hib capsular polysaccharide, and changes it to a T-cell dependent antigen. In clinical use, the conjugate vaccines are immunogenic in infancy, induce immunologic memory, and protect efficiently from invasive infections. They even seem to reduce oropharyngeal carriage of Hib bacteria. Wide-scale use of Hib conjugate vaccines has demonstrated their safety and low reactogenicity. Studies to combine them with other childhood vaccines are in progress. First signs of reduction of severe Hib infections can already be seen in countries where Hib conjugate vaccines are in wide use.

Bacterial Capsules↗

PubMedDate not supplied

B7.1/NHS76: a new costimulator fusion protein for the immunotherapy of solid tumors.

Tumor evasion from immune surveillance is due to the anergic status of tumor-infiltrating lymphocytes, especially T cells. Inappropriate or absent expression of costimulatory molecules such as B7.1 and B7.2 lead to anergy and apoptosis of tumor-infiltrating T cells. To reverse this situation, a tumor-targeted fusion protein, human B7.1/NHS76, was generated by molecular engineering, which retains both the costimulatory activity of B7.1 and the tumor-targeting ability of NHS76 antibody. NHS76 is a human tumor necrosis therapy monoclonal antibody derived from phage display, and is capable of binding intracellular antigens, which are accessible and abundant in necrotic regions of tumors. As human B7.1 can interact functionally with murine B7.1 counter-receptors, the immunotherapeutic potential of this fusion protein was tested in 3 mouse tumor models (Colon 26, RENCA, and MAD109), and animal studies showed a 35% to 55% reduction in tumor volume. To modulate the immune inhibitory microenvironment in tumors, naturally occurring CD4+ CD25+ Treg cells were depleted by cytotoxic CD4 or CD25 antibodies. Combination therapy with anti-Treg and B7.1/NHS76 produced complete regression of established tumors and was associated with increased effector T-cell infiltration in tumors. Rechallenge experiments performed 3 months after mice attained complete remission by combination therapy showed that immunologic memory was established by these treatments. These studies indicate that the targeting of B7.1 to necrotic areas of tumors, where both the release of tumor antigens and infiltrating lymphocytes are prevalent, may be a new approach for the immunotherapy of solid tumors. Our results also suggest that the manifestation of immune-inhibitory factors such as the presence of Treg cells at the tumor site and associated draining lymph nodes may be a major cause for immune system failure to eradicate solid tumors.

Animals↗

PubMed2004

Duration of hepatitis B immunity in low risk children receiving hepatitis B vaccinations from birth.

BACKGROUND: The duration of protection after hepatitis B vaccination of infants is unknown. METHODS: We determined antibody to hepatitis B surface antigen (anti-HBs) at 4-13 years of age in 363 low risk children who had been vaccinated starting at birth with hepatitis B vaccine. Those with nonprotective titers (<10 mIU/mL) received a booster dose. We similarly followed 16 children of hepatitis B surface antigen (HBsAg)-positive mothers. RESULTS: Of low risk infants receiving a plasma-derived vaccine, 41% (42 of 102) of those whose primary response was unknown and 24% (4 of 17) who had initially responded retained protective titers (> or = 10 mIU/mL) of anti-HBs at 9 and 13 years, respectively. Of those who did not have protective antibody titers, 61% (33 of 54) and 67% (8 of 12), respectively, responded to a booster dose. In children of HBsAg-positive mothers, 31% retained protective anti-HBs at 12 years, and 90% (9 of 10) with nonprotective titers responded to a booster. In low risk children initially receiving a recombinant vaccine, 12.5% (26 of 208) and none (0 of 36) retained protective anti-HBs titers at 5 and 7 years of age, respectively. Of those who did not have protective titers, 90% (120 of 134) and 91% (32 of 35), respectively, responded to a booster. CONCLUSIONS: Anti-HBs disappeared by 5 years of age in most children who were vaccinated with hepatitis B vaccine from birth. Although most children showed immunologic memory, one-third failed to demonstrate an anamnestic response to a booster dose. Additional long term studies of low risk infants are needed to determine duration of protection and the necessity for or timing of booster doses.

Alaska↗

PubMed2004

OX40 (CD134) blockade inhibits the co-stimulatory cascade and promotes heart allograft survival.

BACKGROUND: CD134 (OX40) is a member of the tumor necrosis factor receptor superfamily that is expressed as a late event in T-cell activation and contributes to the generation of immunologic memory. CD134 blockade effectively ameliorates inflammation in models of autoimmune disease, but its role in transplantation has been less well studied. METHODS: The authors used an OX40-immunoglobulin (Ig) fusion protein to examine the contribution of this co-stimulatory molecule to the in vitro alloimmune response and studied the ability of CD134 blockade to prevent cardiac allograft rejection in mouse models of heart transplantation using strains representing both major histocompatibility complex (MHC) (BALB/c to CBA/Ca) and minor histocompatibility complex (mHC) (B10.BR to CBA/Ca) antigen mismatches. RESULTS: CD134 upregulation on in vitro alloactivated T cells was delayed compared with CD69 and CD25, and inhibition of T-cell proliferation was critically dependent on the timing of OX40-Ig administration. Heart allograft survival in a fully allogeneic, MHC-mismatched strain combination was not influenced by CD134 blockade alone, but OX40-Ig treatment in the mHC-mismatched model resulted in long-term graft survival (median survival time extended from 14 days to >100 days). Early mononuclear cell infiltration of the graft was similar in both rejecting and long-surviving heart grafts, but OX40-Ig treatment appeared to delay cellular infiltration. CONCLUSIONS: These results show that CD134-CD134L interaction plays an important role in the co-stimulatory cascade and that blockade of this molecular interaction may be of therapeutic value in helping to prevent allograft rejection.

Animals↗

PubMed1986

Allogeneic cell interactions during graft rejection in Callyspongia diffusa (Porifera, Demospongia); a study with monoclonal antibodies.

Many aspects of the cellular immune system in the marine sponge Callyspongia diffusa, have been defined by using artificially transplanted allogeneic tissues. Rejections show specificity of 'non-self' recognition, cytotoxic effector responses and short-term immunological memory. Histological investigations reveal a generalized mesohyl migration to the graft zone where archaeocytes line up at the allogeneic interface. Monoclonal antibodies (mAbs) raised to sponge cells have shown that little or no allogeneic cell mixing occurs at the graft interface and that certain mesohyl cell types do not appear to be directly involved in graft rejections. However, all mesohyl cell types are present in autograft fusion zones and in inflammatory responses to injury. The involvement of only some of the mesohyl cell types in graft rejections suggests specific interactions of an effector 'immunocyte'.

Animals↗

PubMed2006

Are there differences in immune function between continental and insular birds?

Generally, immune system architecture varies with different environments, which presumably reflect different pathogen pressures. Specifically, populations from relatively disease-free, oceanic islands are expected to exhibit reorganized immune systems, which might be characterized by attenuated responses, given the costs of immune function. Some insular animals exhibit an 'island syndrome,' including increased susceptibility to disease, and some insular populations have declined when they failed to resist infection by introduced pathogens. I measured eight indices of immune function (haemolysis, haemagglutination, concentration of haptoglobin and concentration of five leukocyte types) in 15 phylogenetically matched pairs of bird populations from North America and from the islands of Hawaii, Bermuda and the Galápagos. Immune responses were not attenuated in insular birds, and several indices, including the concentration of plasma haptoglobin, were elevated. Thus, I find no support for the specific hypothesis that depauperate parasite communities and the costs of immune defences select for reduced immune function. Instead, I suggest that life on islands leads to an apparent reorganization of immune function, which is defined by increases in defences that are innate and inducible. These increases might signal that systems of acquired humoral immunity and immunological memory are less important or dysfunctional in island populations.

Animals↗

PubMed2001

Mucosal and systemic antibody responses to the lipopolysaccharide of Escherichia coli O157 in health and disease.

Mucosal immunity in the gastrointestinal (GI) tract is a primary defence against GI pathogens. We hypothesise that a mucosal response to lipopolysaccharide (LPS), especially to the common (core) determinants of GI pathogenic Escherichia coli strains, is protective. The aims of this study were to investigate the specificities, levels and development of humoral responses in health and GI disease to the R3 LPS core and O-polysaccharide of E. coli O157. The purpose was to try to predict whether vaccination or passive immunisation might induce protection. Wherever possible, paired whole gut lavage fluid (WGLF) and serum samples were collected for comparison of the mucosal and systemic responses. Matched saliva samples were also collected from some study groups. The patient groups included those with acute E. coli O157 disease (serum only), patients convalescing after E. coli O157 infections, and patients undergoing routine investigation for GI conditions but subsequently shown to be immunologically normal. Some samples of WGLF from patients with Crohn's disease (CRO) and ulcerative colitis (UC) were included to allow comparisons with patients with inflammatory conditions known to alter antibody secretion in the GI tract. The healthy groups from whom serum and saliva only were taken included blood donors, healthy volunteers and a group of slaughterhouse workers. This latter group was likely to have been exposed regularly to faecal bacteria from animals and antibody specificities might have been expected to be different from other healthy individuals. Levels and classes of antibodies were determined by ELISA with microtitration plates coated with polymyxin complexes of whole LPS extracted from E. coli O157 and LPS from the E. coli R3 rough mutant. Antibodies of IgG and IgM classes were measured in serum and IgA was measured in WGLF and saliva. IgG antibodies to the O157 LPS and the R3 core oligosaccharide were detected in the serum of healthy blood donors. Patients with acute E. coli O157 disease showed elevated levels of serum IgM to O157 LPS and R3, with IgG levels raised only to R3. In serum from convalescent patients, IgG to O157 LPS was significantly above the control groups only in the period 6-16 weeks after infection. Total IgA levels were similar in WGLF specimens from all groups, except the patients with UC, whose levels were much higher. Specific IgA levels were higher in the E. coli O157 convalescent group, but there were no significant correlations overall. UC patients had significantly lower levels of IgA to O157 and CRO patients had higher O157 IgA levels than UC patients and healthy volunteers. In serum, inhibition of ELISA showed that the response to the O157 LPS was due in part to a response to the R3 oligosaccharide component. This response was much more pronounced in the healthy and non-O157 groups than in convalescent patients. There was no correlation between specific IgA antibody levels in saliva and matched specimens of WGLF, and levels in sequential saliva specimens fluctuated widely. The significant IgG and IgA responses to the R3 core suggest that there is immunological memory to this oligosaccharide LPS component which may have a role in protection against E. coli LPS both systemically and locally in the GI tract. Boosting of this mucosal response to the LPS core, either naturally through exposure or by active or passive immunisation, may confer protection. Finally, antibody responses to E. coli O157 must be interpreted with caution, as the response detected is a sum of responses to the O-specific polysaccharide and the R3 core.

Adolescent↗

PubMed1975

Nonspecific elicitation of antibody-forming cells in the mouse spleen by bacterial lipopolysaccharide.

Mechanisms of nonspecific elicitation of anti-sheep erythrocyte (SRBC) hemolytic antibody plaqueforming cells (PFC) in mouse spleens with an injection of bacterial endotoxin (lipopolysaccharide (LPS)) were studied in comparison with the genesis of naturally occurring "background" PFC in normal mouse spleens and of rapidly arising PFC in mouse spleens after immunization with SRBC. The cytokinetic pattern of anti-SRBC PFC response after an injection of LPS was quite different from that of the response elicited after immunization with SRBC. In addition, even though LPS nonspecifically elicited anti-SRBC PFC response in mice, LPS could not confer any immunological memory on mouse immunocytess for a "secondary-type" anti-SRBC PFC response to restimulation with LPS or SRBC. The administration of rabbit anti-mouse thymocyte immunoglobulin or anti-SRBC antiserum in mice markedly suppressed the PFC response after immunization with SRBC, but did not do so after stimulation with LPS. Neonatally thymectomized mice could still respond to stimulation with LPS, producing anti-SRBC PFC in their spleens. Injections of actinomycin D or cyclophosphamide into mice resulted in obvious reductions of the PFC responses elicited by either LPS or SRBC. However, injections of these immunosuppressive antisera or drugs did not affect the number of anti-SRBC PFC in normal mouse spleens. These results suggest that the genesis of anti-SRBC PFC developed under different conditions, i.e., background PFC, LPS-stimulated PFC, and antigen-stimulated PFC, are quite different from each other, and that the nonspecific elicitation of anti-SRBC PFC by LPS does not require the helper function of T lymphocytes. No obvious difference, however, was observed in the time of ontogenic maturation among these three different anti-SRBC PFC in the mouse spleens judging from when they were first manifested after birth.

Animals↗